Viral encephalitis is rising as a cause for alarm, with the recent emergence of a series of new agents of serious CNS infection, including several zoonotic viruses that cause lethal encephalitis in humans. One virus that has long been a human pathogen remains at the top of the list: measles. Measles virus (MV) causes disease worldwide despite efforts towards eradication by vaccine, largely because it is spread so readily between people. While the disease is generally self-limited, several serious complications involve the CNS and lead to sequelae or death. These CNS manifestations may occur early after infection, in the case of acute encephalomyelitis, or years after infection, as a result of viral persistence in subacute sclerosing panencephalitis. The third form of MV-induced CNS disease, progressive infectious encephalitis, occurs 1 to 6 months following measles infection, and is problematic in an increasing population of immunocompromised patients. There is no specific therapy for acute or persistent CNS complications of measles. We propose to apply the results of our fundamental research to the development of a new antiviral strategy for measles CNS infection. The proposal is based on our recent discovery that attachment of a cholesterol group to a peptide fusion inhibitor yields 3 major advantages: (1) increased potency, (2) localization of the peptide with the virus at the site of fusion activation, and (3) CNS penetration. We showed that cholesterol- tagged peptides are highly effective against measles virus in vitro, and we propose to assess their potential to treat measles infection of the CNS in a transgenic murine encephalitis model expressing the MV receptor human CD150 (SLAM). By combining sequence optimization with cholesterol tagging, we propose to develop highly effective peptide fusion antivirals that inhibit MV in vitro, and to test their therapeutic potential in a relevant animal model of MV encephalitis. We will pursue preclinical development of our lead therapeutic candidate by: Aim 1. Lead optimization of MV fusion inhibitor peptides targeted to the plasma membrane, using (a) biophysical analysis-guided sequence optimization, and (b) membrane targeting. Aim 2. Effectiveness of the fusion inhibitors to protect from measles encephalitis induced by wild type MV in a transgenic murine model. We will assess (a) bioavailability of the targeted peptides, and (b) efficacy in challenge experiments in a CD150(SLAM) transgenic mouse model. We will thereby obtain proof of principle for efficacy, allowing us to select peptides for advancement that have the most in vivo potential. PUBLIC HEALTH RELEVANCE: Viral encephalitis is rising as a cause for alarm, with the recent emergence of a series of new agents of serious central nervous system (CNS) infection, including West Nile virus, Chikungunya virus, and other zoonotic viruses that cause lethal encephalitis in humans. One virus that has long been a human pathogen remains at the top of the list: measles. Currently there is no specific treatment for the important CNS disease caused by measles. Several of our recent advances, including discovery of a way to develop effective paramyxovirus fusion inhibitors and to deliver these molecules across the blood brain barrier, are now ready to be applied to measles diseases of the CNS. These strategies are worth urgently pursuing to develop targeted antiviral compounds for measles. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.